N,n{40 -alkylenebis(pyridine-carboxamides)

ABSTRACT

N,N&#39;&#39;-Alkylenebis(alkoxypyridinecarboxamides) where alkylene has from seven to ten carbon atoms inclusive, having endocrinological properties, are prepared either by reacting an alkylenediamine with an alkoxypyridinecarboxylic acid or stepwise by reacting an alkylenediamine with an hydroxypyridinecarboxylic acid, halogenating the resulting N,N&#39;&#39;alkylenebis(hydroxypyridinecarboxamide) to form the corresponding N,N&#39;&#39;-alkylenebis(halopyridinecarboxamide) and reacting said halopridinecarboxamide with a metal lower-alkoxide.

United States Patent Lesher I 54] N,N '-ALKYLENEBIS(PYRIDINE-CARBOXAMIDES) [72] Inventor: George Y. Lesher, Schodack, NY.

[73] Assignee: Sterling Drug Inc., New York, NY.

[22] Filed: Feb. 25, 1971 [21] Appi. No.: 119,027

[52] US. CI.......260/295 AM, 260/2955 A, 424/263 [51] Int. Cl. ..C07d31/44 [58] Field of Search ..260/295 AM, 295.5 A

[56] References Cited FOREIGN PATENTS 0R APPLICATIONS 533,436 12/1954Belgium "260/295 AM 51 Oct. 10,1972

Primary Examiner-Henry R. Jiies Assistant ExaminerRobert T. BondAttorney-Elmer .I. Lawson, B. Woodrow Wyatt, Thomas L. Johnson, RobertK. Bait, William G. Webb, Frederik W. Stonner, Theodore C. Miller, RogerT. Wolfe and Lynn '1. Fletcher [57] ABSTRACT 16 Claims, No Drawings 1N,N '-ALKYLENEBIS(PYRIDINE'CARBOXAMIDES) This invention relates tocompositions of matter known in the art of chemistry as N,N-alkylenebis(pyridinecarboxamides) and to their preparation.

The invention in its composition aspect resides in compounds havingformula I R R 0 W0 May-Ml where R is hydrogen or lower-alkyl, R islower-alkyl and Y is alkylene having from seven to ten carbon atomsinclusive and having at least seven carbon atoms between its twoconnecting linkages. The compounds of this composition aspect of theinvention when tested according to standard endocrinological evaluationprocedures in female rats have been found to be useful in havingantifertility activity.

"Lower-alkyl", as used herein, is an alkyl radical, preferably havingfrom one to six carbon atoms, which can be arranged as straight orbranched chains, including, for instance, but without limiting thegenerality of the foregoing, methyl, ethyl, n-propyl, isopropyl, 2butyl,isobutyl and n-hexyl.

Alkylene", as used herein, as designated by Y in formula 1, is analkylene radical having from seven to ten carbon atoms and having atleast seven carbon atoms between its two connecting linkages,illustrated y The invention sought to be patented in its process aspectis described as residing in the process for the preparation of thecomposition aspect of the invention, that is, the compound of formula Iwhich comprises either reacting a diamine of the formula ll RNH-Y-NHR nwith at least two molar equivalents of a' lower-alkoxypyridine-carboxylating agent or stepwise reacting a diamine of saidformula ll with at least two molar equivalents of anhydroxypyridinecarboxylating agent, halogenating the resultingN,N'-alkylenebishydroxypyridinecarboxamide) to form the correspondingN,N'-alkylenebis(halopyridinecarboxamide) and reacting saidhalopyridinecarboxamide with a metal lower-alkoxide.

Another aspect of the composition aspect of the invention resides in theintermediate N,N'alkylenebis(hydroxyor halo-pyridinecarboxamides of theformula III III where Q is hydroxy or halo, R is hydrogen or lower alkyland Y is alkylene having from seven to ten carbon atoms inclusive andhaving at least seven carbon atoms between its two connecting linkages.Q when halo can be chloro, bromo, fluoro or iodo, preferably chloro.

The nature of the starting materials, mode of synthesis, results ofelementary analyses, examination of the final products of formula I byinfrared and nuclear magnetic resonance spectrographic analyses, alltaken together, confirm the molecular structure assigned to thesecompounds.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art ofmedicinal chemistry to make and use the same, as follows.

The intermediate diamines and alkoxyor hydroxypyridinecarboxylic acidare either commercially available or readily prepared using knownstarting materials and using conventional methods, as illustratedhereinbelow in the specific examples.

The compounds of formula I are useful in the free base form or in theform of their acid-addition salts, and both forms are within the purviewof the invention, and are considered to be one and the same invention.The use of the salt form inherently amounts to use of the base form. Theacids which can be used to prepared the acid-addition salts arepreferably those which produce, when combined with the free base,pharmaceutically acceptable salts, that is, salts whose anions arerelatively innocuous to the animal organism in pharmaceutical doses ofthe salts, so that the beneficial properties inherent in the free baseare not vitiated by side effects ascribable to the anions; in otherwords, the latter do not substantially affect the pharmaceuticalproperties inherent in the cations. Appropriate pharmaceuticallyacceptable salts within the scope of the invention are preferably thosederived from mineral acids such as hydrochloric acid, hydrobromic acid,hydriodic acid, nitric acid, phosphoric acid, sulfamic acid, andsulfuric acid; and organic sulfonic acids such as methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,naponic acid (1,4- naphthalenedisulfonic acid), and the like, giving thehydrochloride, hydrobromide, hydriodide, nitrate, phosphate, sulfamate,sulfate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and naponate, respectively.

The acid-addition salts are prepared preferably by reacting the freebase and acid in an organic solvent, e.g., ethanol, Z-propanol, acetone,etc., in which case the salt separates directly or can be obtained byconcentration of the solution.

The final products of formula I are prepared in one process aspect ofthe invention by reacting the appropriate diamine of formula ll in onestep with at least two molar equivalents of a(lower-alkoxy)pyridinecarboxylating agent, preferably alower-alkoxypyridinecarboxylic acid. The reaction is carried out bymixing the reactants preferably in a suitable solvent, for example,dimethylformamide, tetrahydrofuran, benzene, ethylene dichloride, andthe like, and either in the absence of or preferably in the presence ofa dehydrating or an activating agent, e.g., dicyclohexylcarbodiimide,l,l'-carbonyldiimidazole, and the like. The reaction is carried outpreferably at room temperature, about 202S C. although highertemperatures up to about C. can be used.

In another process aspect of the invention involving several steps thecompounds of formula l are prepared by first reacting said diamine offormula ll with at least two molar equivalents of anhydroxypyridinecarboxylating agent, preferably anhydroxypyridinecarboxylic acid, this first step being carried out likethe abovedescribed reaction of said diamine with a(lower-alkoxylpyridinecarboxylating agent. The second step consists ofhalogenating the resulting N,N'-alkylenebis(hydroxypyridinecarboxamide);this halogenation is conveniently carried out using phosphoruspentachloride and phosphorus oxychloride, by first adding the phosphorusoxychloride to a chilled dry mixture of saidalkylenebis(hydroxypyridinecarboxamide) and phosphorus pentachloride,next gently warming the reaction mixture with stirring and then heatingthe mixture with stirring on a steam bath. Alternatively, thehalogenation can be run using phosphorus oxychloride or phosphorusoxybromide under pressure, or using triphenylphosphine dibromide ordichloride. In the third step theN,N'-alkylenebisfhalopyridinecarboxamide) is reacted with an alkylatingagent, preferably an alkali lower-alkoxide to form theN,N'-alkylenebis(alkoxypyridinecarboxami de); the reactants arepreferably mixed cautiously in a suitable solvent, for example,tetrahydrofuran or a lower-alkanol (corresponding to the alkanol used toprepare the metal alkoxide), in an ice bath and the mixture is thengently heated on a steam bath under reflux with stirring.

The best mode contemplated for carrying out the invention will now beset forth as follows.

1. N,N-Heptamethylenebis(S-methoxypicolinamide) To a mixture containingl l.7 g. of S-methoxypicolinic acid hydrochloride and 250 ml. ofdimethylformamide was added 5.2 g. of sodium bicarbonate and theresulting mixture was stirred at room temperature for thirty minutes toprovide a solution of S-methoxypicolinic acid in free base form. To thestirred mixture was added 10.0 g. of l,l-carbonyldiimidazole andstirring was continued for l hour. Next, 4.0 g. of l,7-heptanediaminewas added and the resulting mixture was stirred at room temperature for2 days. The reaction mixture was then poured into two volumes of water.The resulting crystalline precipitate was collected, washed successivelywith water and ether, recrystallized from isopropyl acetate andair-dried. This product was purified as follows: It was dissolved bywarming it with 2N hydrochloric acid; the solution was cooled, washedtwice with ether and made basic with solid sodium bicarbonate; theseparated product was collected, washed with nhexane, was slurried indry ether, collected and dried overnight in a vacuum desiccator to yield5.7 g. of N,N'-heptamethylenebis(5methoxypicolinamide, mp. 49-51" C.Reaction of this product with more than a twofold excess of hydrogenchloride yields its dihydrochloride. Other acid-addition salts aresimilarly prepared by reaction with the appropriate acid.

The above intermediate 5-methoxypicolinic acid as its hydrochloride wasprepared as follows. To a mixture containing 42.5 g. ofS-hydroxypicolinic acid and 1 liter ofanhydrous benzene was added 745 g.of silver oxide and the resulting mixture was stirred for 30 minutes andthen treated with 9L4 g. of methyl iodide. The resulting mixture wasstirred for 16 hours at room temperature followed by refluxing on asteam bath for 24 hours with stirring. The reaction mixture was filteredto remove the silver oxide which was then washed with dry benzene. Thefiltrate was concentrated in vacuo to remove the benzene and excessmethyl iodide. The residue, which crystallized on cooling, was treatedwith 330 ml. of 2N sodium hydroxide solution and the mixture heated on asteam bath overnight. The mixture was made acidic with concentratedhydrochloric acid and concentrated in vacuo to dryness. The residue wasdissolved in boiling ethanol and filtered. The filtrate was treated withdecolorizing charcoal and filtered. The filtrate was concentrated todryness and the residue was slurried in isopropyl alcohol and themixture filtered. The solid was washed successively with isopropylalcohol and ether, and then air-dried to yield, as a white powder, 22.0g. of S-rnethoxypicolinic acid as its hydrochloride, m.p. 2l3-2l5" C.

Following the above procedure for the preparation of S-methoxypicolinicacid using corresponding molar equivalent quantities of the appropriatehydroxypyridinecarboxylic acid, lower-alkyl halide (iodide, bromide orchloride), the following (lower-alkoxy)pyridinecarboxylic acids in theform of their hydrohalide salts are prepared: S-methoxypicolinic acid,5-ethoxypicolinic acid, S-n-propoxypicolinic acid, 5-isopropoxypicolinicacid;S-n-butoxypicolinic acid, S-isobutoxypicolinic acid,S-n-hexoxypicolinic acid, 3- methoxypicolinic acid,Z-methoxyisonicotinic acid, 3- ethoxyisonicotinic acid,6-methoxynicotinic acid and 6-ethoxynicotinic acid.

2A. N,N'-Heptamethylenebis(b-hydroxynicotinamide) To a stirredsuspension containing l3.9 g. of G-hydroxynicotinic acid in 500 ml. ofdimethylformamide was added 16.2 g. of L1 '-carbonyldiimidazole and theresulting mixture was stirred for 30 minutes at room temperaturewhereupon the o-hydroxynicotinic acid dissolved to give a pale yellowsolution. To the solution was added with stirring 6.5 g. of1,7-heptanediamine and a small quantity ofdimethylformamide whereupon apale yellow gelatinous precipitate formed, most of which dissolved afterstirring the mixture for about I hour, at which time a solid began toseparate. The mixture was stirred at room temperature for 92 hours andthe yellowish white solid was collected and taken up in 335 ml. of 2.5percent potassium hydroxide solution. The alkaline solution was filteredthrough infusorial earth using a sintered glass funnel. The filtrate wasacidified with 3N hydrochloric acid with stirring. The separated whitesolid was collected, washed with fresh water, air-dried, recrystallizedfrom ml. of acetic acid, washed with acetone and dried in a vacuum ovenat llU C. to yield 12.4 g. ofN,N'-heptamethylenebis(o-hydroxynicotinamidel, mp. 272273C Following theprocedure descri for the preparation of hydroxynicotinamide) bed inExample 2A N,N'-heptamethylenebis(6- but using corresponding molarequivalent quantities of the appropriate hydroxypyridinecarboxylic acidin place ofo-hydroxynicotinic acid and the appropriate alkvlenediaminein place of |,7-heptanediamine. the followingN,N'-alkylenebis(hydroxypyridinecarboxamides) are formed:N,N-heptamethylenemN,N'-dimethylbis(6-hydroxynicotinamide N ,N-heptamethylenebis( Z-hydroxynicotinamide),N,N-heptamethylenebis(4-hydroxynicotinamide),N,N-heptamethylenebis(4-hydroxypicolinamide),N,N'-heptamethylenebis(S-hydroxypicolinamide),N,N-hepta-methylene-N,N'-dimethylbis(S-hydroxypicolinamide),N,N'-heptamethylenebis(6-hydroxypicolinamide),N,N'-octamethylenebis(o-hydroxynicotinamide), N,N-nonamethylenebis(d-hydroxynicotinamide), N,N-decamethylenebis(6-hydroxynicotinamide),N,N-heptamethylene-bis(Z-hydroxyisonicotinamide) and N,N-heptamethylenebis( 3-hydroxyisonicotinamide 2B.N,N'-l-leptamethylenebis( fi-chloronicotinamide) To a dry mixturecontaining 18.6 g. of N,N-heptamethylenebis(6-hydroxynicotinamide) and37.0 g. phosphorus pentachloride and placed in an ice bath was added22.0 g. of phosphorus oxychloride, and the flask containing theresulting mixture was shaken until the mixture was mixed as well aspossible. The flask was then placed in a pan of warm water for aboutminutes and was next heated gently on a steam bath with stirringovernight. The mixture was cooled and poured into 800 g. of crushed ice.The resulting mixture was stirred while allowing the ice to melt. Thesolid was collected, washed with fresh water, air-dried, recrystallizedfrom 130 ml. of dimethylformamide using decolorizing charcoal, washedwith acetone and dried in a vacuum oven to yield 14.8 g. ofN,N'-heptamethylenebis(fi-chloronicotinamide), m.p. 202-204 C.

Following the procedure described in Example 2B but using correspondingmolar equivalent quantities of the appropriateN,N'-alkylenebis(hydroxypyridinecarboxamide) in place ofN,N'-heptamethylenebis(6- hydroxynicotinamide), the followingN,N'-alkylenebis(chloropyridinecarboxamides) are obtained:N,N-heptamethylene-N,N"dimethylbis(- chloronicotinamide),N,N'-heptamethylenebis(2- chloronicotinamide), N,N'-heptamethylenebis(4-chloronicotinamide), N,N'-heptamethylene-bis(4- chloropicolinamide),N,N'-heptamethylenebis( 5- chloropicolinamide),N,N'-heptamethylene-N,N'- dimethylbis( 5-chloropicolinamide N,N'-heptamethylenebis( 6-chloropicolinamide),N,N'-octamethylenebis(6-chloronicotinamide), N,N- nonamethylenebis(o-chloronicotinamide N ,N decamethylenebis( -chloronicotinamideN,N-heptamethylenebis(Lchloroisonicotinamide) and N,N-heptamethylenebis( 3-chloroisonicotinamide). Following the proceduredescribed in Example 2B but using triphenylphosphine dibromide as thehalogenating agent, there is obtained N,N'-heptamethylenebis(6-brornonicotinamide).

2C. N,N'-Heptamethylenebis(6-methoxynicotinamide) To 750 ml. of methanolchilled in an ice bath was cautiously added with stirring 30 g. ofsodium methoxide. To this cooled solution was added with stirring 14.8g. of N,N'-heptamethylenebis(6-chloronicotinamide). The resultingreaction mixture was gently heated on a steam bath and was then refluxedon the steam bath with stirring for 72 hours. The reaction mixture wasallowed to cool to room temperature and then poured into 2,500 ml. ofwater. The resulting suspension was stirred for 3 hours and the whitesolid was collected, rinsed with a little fresh water, air-dried,recrystallized once from 650 ml. of acetonitrile, dried in a vacuumoven, recrystallized a second time from 350 ml. of acetonitrile andair-dried in a vacuum oven to yield 7.9 g. ofN,N'-heptamethylenebis(6-methoxynicotinamide), m.p. l62.5l63 C. Reactionof this product with more than a two-fold excess of hydrogen chlorideyields its dihydrochloride. Other acid-addition salts are similarlyprepared by reaction with the appropriate acid.

Following the example described in Example l for the preparation ofN,N'-heptamethylenebis(S-methoxypicolinamide) but using correspondingmolar equivalent quantities of the appropriate alkoxypyridinecarboxylicacid in place of S-methoxypicolinic acid and using the appropriatealltylenediamine in place of 1,7-heptanediamine, theN,N'-alkylenebis(alkoxypyridinecarboxamides) of Examples 3-17 areprepared.

3. N,N'-l-leptamethylenebis(imethoxynicotinamide).

4. N,N '-Octamethylenebis( S-methoxypicolinamide 5.N,N'-Nonamethylenebis(S-methoxypicolinamide).

6. N,N'-Decamethylenebis( S-methoxypicolinamide).

7. N ,N '-Heptamethylenebis( 5-ethoxypicolinamide 8.N,N'-I-leptamethylenebis(S-n-propoxypicolinamide).

9. N,N'-Heptamethylenebis(S-isopropoxypicolinamide).

l0. N,N'-Heptamethylenebis(5-n-butoxypicolinamide).

l l. N,N'-Heptamethylenebis(S-isobutoxypicolinamide).

l2. N,N'-Heptamethylenebis(S-n-hexoxypicolinamide).

l 3. N,N'-l-leptamethylenebis(3-methoxypicolinamide).

l4. N,N-l-leptamethylenebis(Z-methoxyisonicotinamide).

15. N ,N'-Heptamethylenebis( 3-ethoxyisonicotinamide).

l6. N,N-Heptamethylene-N,N '-dimethylbis( 5- methoxypicolinamide l7.N,N'-Heptamethylene-N,N-diethylbis(6- methoxynicotinamide).

Following the procedure described in Example 2C for the preparation ofN,N'-heptamethylenebis(6- methoxynicotinamide) but using correspondingmolar equivalent quantities of the appropriateN,N-alkylenebis(chloropyridinecarboxamide) in place ofN,N'-heptamethylenebis(6-chloronicotinamide) and using the appropriatealkali, e.g., sodium, alltoxide in place of sodium methoxide, thefollowing N,N-alkylenebis(alkoxypyridinecarboxamides) of Examples [8-34are obtained.

18. N,N'-Heptamethylenebis(6ethoxynicotinamide).

l 9. N,N'-Heptamethylenebis( 6-n-propoxynicotinamide).

20. N,N'-Heptamethylenebis(6-n-butoxynicotinamide).

2 l N,N'-Heptamethylenebis(fi-isobutoxynicotinamide).

22. N,N'-Heptamethylenebis(-n-hexoxynicotinamide).

23. N,N'-Octamethylenebis(G-methoxynicotinamide).

24. N,N-Nonamethylenebis(o-methoxynicotinamide).

25. N.N'-Dccnmethylenehin( fi-mcthnxynicotinamide).

26. N,N-Heptamethylenebis(2-methoxynicotinamide).

27. N,N'-l-leptamethylenebis(4-methoxynicotinamide).

28. N,N'-Heptamethylenebis(4-methoxypicolinamide).

29. N,N'-Heptamethylenebis( o-methoxypicolinamide).

30. N,N'-l-leptamethylenebis(2-methoxyisonicotinamide).

3 l. N,N'-Heptamethylenebis(3-ethoxyisonicotinamide).

32. N,N'-Heptamethylene-N,N'-dimethylbis( 6- methoxynicotinamide 33.N,N'-Heptamethylene-N,N'-dimethylbis(5- methoxypicolinamide.

34. N,N'-Heptamethylenebis(S-methoxypicolinamide).

The antifertility activity of the compounds of the invention wasdetermined by the following standard test procedure using female ratswhich are medicated prior to, during and after the mating period. Therats are autopsied on the l4th post mating day and the uteri areexamined for evidence of pregnancy. The procedural details are asfollows. A colony of sexually mature female rats of the Sprague-Dawieystrain weighing 200-300 grns. are maintained on routine laboratory care.Daily vaginal smears are examined to record the cyclic characteristicsof each rat. A given test is composed of rats which have exhibited aminimum of 3 coincidental estrus cycles. Three days prior to an expectedestrus the rats to be placed on test are grouped, housed individuallyand placed on medication. The medication consists of a test compound,prepared as a solution or suspension in a suitable vehicle, administeredorally via stomach tube once daily for a total of 8 medications in a 10day period (Sunday medications are omitted). One group receives only thevehicle in a like manner to serve as a control. Late in the after noonof the day preceding the expected estrus a mature proven fertile male ishoused with each female overnight. The following morning all males areremoved and a vaginal smear of each female is examined for the presenceof spermatozoa as evidence that insemination has occurred. Medication ofall inseminated rats is continued through the 7th post insemination day.The rats are autopsied 7 days after the last medication and the uteriremoved and examined for evidence of pregnancy. The number ofimplantation sites, number of resorption sites, total number of fetusesand the number of viable fetuses are recorded. When tested by thisprocedure, the compounds of the invention were found to haveantifertility at dose levels ranging from about 50 to 300 mg. per kg.per day.

The actual determination of the numerical antifertility data definitivefor a particular compound is readily obtained by standard testprocedures, referred to above, by technicians versed in endocrinologicaltest procedures, without any need for any extensive experimentation.

The compounds of the invention can be prepared for use by conventionalpharmaceutical procedures: that is, by dissolving or suspending them ina pharmaceutically acceptable vehicle, e.g., aqueous alcohol, glycol,oil solution, or oil-water emulsion, for parenteral or oraladministration; or by incorporating them in unit dosage form as tabletsor capsules for oral administration either alone or in combination withconventional adjuvants, e.g., calcium carbonate, starch, lactose, talc,magnesium stearate, gum acacia, and the like.

lclaim:

l. N,N'-Alkylenebis( alkoxypyridinecarboxamide) of the formula where Ris hydrogen or lower-alkyl, R is lower-alkyl and Y is alkylene havingfrom seven to ten carbon atoms inclusive and having at least sevencarbon atoms between its two connecting linkages.

2. N,N'-Alkylenebis[ 5-(lower-aikoxy)picolinamide] according to claim 1.

3. N,N'Alkylenebis[6-(lower-alkoxy)nicotinamide] according to claim 1.

4. A compound according to claim 1 where, R is hydrogen, R is methyl andY is heptamethylene.

5. N,N'-Heptamethylenebis(S-methoxypicolinamide) according to claim 4.

6. N,N-Heptamethylenebis( b-methoxynicotinamide) according to claim 4.

7. A process for the preparation of a compound according to claim 1which comprises either reacting a diamine of the formula RNH-Y-NHR witha lower-alkoxypyridinecarboxylating agent or reacting a diamine of saidformula with an hydroxypyridinecarboxylating agent, halogenating theresulting N,N'-alkylenebis(hydroxypyridinecarboxamide) to form thecorresponding N,N'-alkylenebis(halopyridinecarboxamide) and reactingsaid halopyridinecarboxarnide with a metal lower-alkoxide.

8. A process according to claim 7 which comprises reacting1,7-heptanediamine with 5-(lower-alkoxy)picolinic acid to formN,N'-heptamethylenebis[5- (lower-alkoxy)picolinamide1.

9. A process according to claim 7 which comprises reactingl,7-heptanediamine with S-methoxypicolinic acid to formN,N'-heptamethylenebis(S-methoxypicolinamide).

10. A process according to claim 7 which comprises reactingl,7-heptanediamine with o-hydroxynicotinic acid to formN,N'-heptamethylenebis(6-hydroxynicotinamide), chlorinating said-hydroxynicotinamide to prepare the correspondingN,N'-heptamethylenebis(6-chloronicotinamide), and reacting said-chloronicotinamide with an alkali lower-alkoxide to formN,N'-heptamethylenebis[6-(lower-alkoxy)nicotinamide].

11. A process according to claim 7 which comprises reactingl,7-heptanediamine with 6-hydroxynicotinic acid to formN,N-heptamethylenebis(fi-hydroxynicotinamide), chlorinating saidfi-hydroxynicotinamide to prepare the correspondingN,N'-heptamethylenebis(6-chloronicotinamicle) and reacting said6-chloronicotinamide with an alkali methoxide to formN,N'-heptamethylenebis(6-methoxynicotinamide).

l2. N,N-Alkylenebis(hydroxyor halo-pyridinecarboxamide) of the formula RR O qgnsai q N N r

2. N,N''-Alkylenebis(5-(lower-alkoxy)picolinamide) according to claim 1.3. N,N''-Alkylenebis(6-(lower-alkoxy)nicotinamide) according to claim 1.4. A compound according to claim 1 where, R is hydrogen, R'' is methyland Y is heptamethylene. 5.N,N''-Heptamethylenebis(5-methoxypicolinamide) according to claim
 4. 6.N,N''-Heptamethylenebis(6-methoxynicotinamide) according to claim
 4. 7.A process for the preparation of a compound according to claim 1 whichcomprises either reacting a diamine of the formula RNH-Y-NHR with alower-alkoxypyridinecarboxylating agent or reacting a diamine of saidformula with an hydroxypyridinecarboxylating agent, halogenating theresulting N,N''-alkylenebis(hydroxypyridinecarboxamide) to form thecorresponding N,N''-alkylenebis(halopyridinecarboxamide) and reactingsaid halopyridinecarboxamide with a metal lower-alkoxide.
 8. A processaccording to claim 7 which comprises reacting 1,7-heptanediamine with5-(lower-alkoxy)picolinic acid to formN,N''-heptamethylenebis(5-(lower-alkoxy)picolinamide).
 9. A processaccording to claim 7 which comprises reacting 1,7-heptanediamine with5-methoxypicolinic acid to formN,N''-heptamethylenebis(5-methoxypicolinamide).
 10. A process accordingto claim 7 which comprises reacting 1,7-heptanediamine with6-hydroxynicotinic acid to formN,N''-heptamethylenebis(6-hydroxynicotinamide), chlorinating said6-hydroxynicotinamide to prepare the correspondingN,N''-heptamethylenebis(6-chloronicotinamide), and reacting said6-chloronicotinamide with an alkali lower-alkoxide to formN,N''-heptamethylenebis(6-(lower-alkoxy)nicotinamide).
 11. A processaccording to claim 7 which comprises reacting 1,7-heptanediamine with6-hydroxynicotinic acid to formN,N''-heptamethylenebis(6-hydroxynicotinamide), chlorinating said6-hydroxynicotinamide to prepare the correspondingN,N''-heptamethylenebis(6-chloronicotinamide) and reacting said6-chloronicotinamide with an alkali methoxide to formN,N''-heptamethylenebis(6-methoxynicotinamide). 12.N,N''-Alkylenebis(hydroxy- or halo-pyridinecarboxamide) of the formulawhere Q is hydroxy or halo, R is hydrogen or lower-alkyl and Y isalkylene having from seven to ten carbon atoms inclusive and having atleast seven carbon atoms between its two connecting linkages. 13.N,N''-Alkylenebis(5-hydroxypicolinamide) according to claim
 12. 14.N,N''-Alkylenebis(5-halopicolinamide) according to claim
 12. 15.N,N''-Alkylenebis(6-hydroxynicotinamide) according to claim
 12. 16.N,N''-Alkylenebis(6-halonicotinamide) according to claim 12.